1. Field of the Invention
The invention provides a novel class of compounds and compositions that are useful in the treatment or prevention of diseases or disorders associated with kinases, particularly GSK3β, c-Abl, HER-1, HER-2, KDR, Flt-3, c-Raf-1, PDGFR-β, c-Kit, Flt-4, Flt-1, Tek, c-src, CDK1, PDK1, FGFR-1, FGFR-2, Fer, MAP3K13, EPHA7 and c-Met kinases. The invention further relates to a method of using compounds of the invention to induce neurogenesis in embryonic stem cells.
2. Background
Kinases are involved in many aspects of cellular metabolism, proliferation, differentiation and development. A partial, non-limiting list of kinases include GSK-3β, c-Abl, HER-1, HER-2, KDR, Flt-3, c-Raf-1, PDGFR-β, c-Kit, Flt-4, Flt-1, Tek, c-src, CDK1, PDK1, FGFR-1, FGFR-2, Fer, MAP3K13, EPHA7 and c-Met. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. Disease areas include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and hormone-related diseases. In particular, kinases have been implicated in various diseases including: diabetes; Alzheimer's disease and mood disorders such as bipolar disorder; CNS disorders such as manic-depressive disorder and neurodegenerative diseases; cardiomyocete hypertrophy; and development and regulation of sperm motility. Further, kinases been implicated in hair loss, schizophrenia and neurotrauma, for example, stroke, traumatic brain surgery and spinal cord trauma. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways, for example, those signaling pathways in which GSK3β, c-Abl, HER-1, HER-2, KDR, Flt-3, c-Raf-1, PDGFR-β, c-Kit, Flt-4, Flt-1, Tek, c-src, CDK1, PDK1, FGFR-1, FGFR-2, Fer, MAP3K13, EPHA7 and c-Met play a role. Accordingly, molecules that modulate the activity of kinase-mediated signaling are useful as therapeutic agents in the treatment of such diseases. Further, the identification of small molecules that permit precise regulation of stem cell renewal and differentiation could facilitate therapeutic applications of stem cells.